Project summary/Abstract: Alzheimer?s disease (AD) and Parkinson?s disease (PD), are estimated to affect 40% and 1% of the United Stated population over 85 years of age, respectively, making them the two most common neurodegenerative diseases [1-6]. The identification of a reliable biomarker for response to interventions in AD and PD will greatly assist in the development of successful disease modifying therapies. Our strong preclinical evidence demonstrates that Nilotinib, a multi-kinase tyrosine kinase inhibitor, increases autophagic clearance of neurotoxic proteins and ameliorates other neurodegenerative pathologies. In humans we have shown that Nilotinib penetrates the brain, inhibits cerebrospinal fluid (CSF) Abelson tyrosine kinase activity, reduces CSF total and phosphorylated tau, stabilizes CSF alpha-synuclein levels, and increases CSF Homovanillic acid, an end byproduct of Dopamine metabolism. MicroRNAs (miRNAs) have recently emerged as attractive candidates as biomarkers in neurodegenerative diseases due to their stability in biological fluids including CSF and plasma. MiRNA are small non-coding RNA whose role is to post-translationally silence expression of gene targets. A pilot study identified 47 miRNA in the CSF of PD and Dementia with Lewy Bodies (DBL) patients differentially expressed after 6 months Nilotinib treatment compared to baseline. Target analysis indicates that many of the down regulated miRNA target genes are associated with autophagy and ubiquitination, agreeing with much of our preclinical work that demonstrates autophagy and ubiquitination leading to proteolysis is inhibited in PD and disinhibited after Nilotinib treatment. Here, I propose to further evaluate the effects of TKI via Nilotinib on gene regulation by sequencing the miRNA in CSF collected from 50 patients enrolled in NCT02954978 to evaluate Nilotinib?s impact in PD and 37 patients enrolled in NCT02954978 to evaluate Nilotinib?s impact in AD. Next- generation sequencing will identify miRNAs that were differentially expressed in Nilotinib treated individuals compared to baseline. Next-generation sequencing will be validated using TaqMan real-time PCR assays. Gene target analysis will be performed to reveal what genes and pathways are associated with the expressed miRNAs. Surrogate protein biomarkers for PD progression will be measured in the CSF using enzyme-linked immunosorbent assays (ELISAs). Together, this wealth of collected data will enable me to correlate miRNA changes to clinical endpoint measures including protein biomarkers and clinical rating scale scores to validate miRNAs as potential reliable biomarkers for the response to TKI via Nilotinib in PD and AD.